Although much is known about the pathophysiological mechanisms underiying traumatic brain injury (TBI), few therapeutic strategies have been found to promote recovery after TBI. The purpose of this study will be to investigate novel therapies that promote recovery of function when initiated in an early or delayed fashion after TBI. In preliminary studies, we found that the transplantation of neural progenitor cells (NPCs) transduced to release a multi-neurotrophin in the injured brain leads to substantial histopathological protection and improvements in cognition even when initiated one week after the traumatic insult. The proposed experiments will extend these exciting findings and provide information regarding the underlying mechanisms for these improvements. This strategy is novel in that few studies have utilized transduced NPCs releasing a multi-neurotrophin that activates all of the neurotrophin receptors to optimally activate cell survival and synaptic plasticity pathways within neurons. We propose three specific aims to test the central hypothesis that transplantation of NPCs expressing a multi-neurotrophin improves functional recovery after TBI. The first aim will identify the optimal conditions for transplantation of the NPCs. We will identify the optimal multi-neurotrophin, cell dosage, therapeutic time window, and rehabilitative strategy that results in the greatest level of behavioral recovery. Our preliminary data indicate that co-transplantation of the NPCs with a soluble, clustered ephrin BS ligand, which promotes cell survival pathways in stem cells in culture and in vivo, may be an innovative strategy to foster survival of the transplanted cells in the injured brain. In the second aim, we will determine which of these transplantation strategies improves histopathological outcome, increases survival of the transplanted NPCs and possibly promotes neurogenesis. The final aim will determine whether the transplantation of the NPCs improves synaptic plasticity in the hippocampus. Thus, the scope of this grant will assess how this cell therapy improves behavioral, morphological, and electrophysiological mechanisms. To thoroughly test the effectiveness of these therapies, potential detrimental side effects will also be assessed, including posttraumatic seizure threshold changes and aberrant axonal sprouting. This project is supported by an established group of investigators who provide the wealth of expertise necessary to conduct this multidisciplinary program in TBI